Dr. Jaeschke and Dr. Williams are experts in the field of acetaminophen hepatotoxicity and we are grateful for the opportunity to respond to their comments regarding our recent article (1). However, we feel they have no grounds for serious concern.
We agree that there was variability in the serum alanine aminotransferase activity after acetaminophen injection and we presented the data for individual mice to allow the reader to appreciate this variability. This highlights the importance of performing a prestudy power calculation based on relevant pilot studies, and our power calculations are included in the article's Materials and Methods section. We included males and females in our experiments, and while individual mice of both sexes developed liver injury, we agree that this may have contributed to the variability in alanine aminotransferase activity. However, all our study groups are age- and sex-matched, and, therefore we do not believe treatment effects can be explained by sex differences. We measured liver glutathione concentration at 6 h after acetaminophen injection as in previous published studies (2), so our data do not allow us to comment on whether the wild-type and knockout mice differed at earlier time points. Drs. Jaeschke and Williams are correct in stating that our control Ab may have reduced liver injury, although this was not formally tested by direct comparison with vehicle pretreatment. This possible reduction in injury was the reason that an appropriate control Ab was essential when we studied the effect of the anti-CD147 Ab. Our data demonstrate a difference between anti-CD147 and control, supporting the role of this receptor in acetaminophen hepatotoxicity.
The role of the immune system in acetaminophen hepatotoxicity is unclear and controversial. This is mentioned in the Discussion section of our article (1): “However, the exact role of inflammation is still an area of controversy [e.g., there is conflicting evidence on the importance of neutrophil infiltration into the liver in acetaminophen poisoning (3, 4)].” We hope that continued study will clarify the situation in mice and, more importantly, produce new therapeutic targets in humans.